A blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings

Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer’s disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; “saved scans”) and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; “positive predictive value”). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.

This table shows, for each biomarker and each screening sensitivity strategy, the negative (NPV) and positive (PPV) predictive values in all included TRIAD participants (n=179).Given the high the a priori defined sensitivities, NPVs were generally very high.When looking at the PPVs, it can be nothed that only pTau217 yield reasonably metrics in comparison to this population's rate of tau-PET positivity (44%).
Confidence intervals were derived with bootstrapping (n=100).PET = positron emission tomography; Aβ = amyloid-beta; pTau = phosphorylated tau; NfL = neurofilament light; GFAP = glial fibrillary acidic protein.This table shows, for each biomarker and each screening sensitivity strategy, the negative (NPV) and positive (PPV) predictive values in all included BioFINDER-2 participants, using a clinically validated visual read method to determine tau-PET positivity (n=539).Given the high the a priori defined sensitivities, NPVs were generally very high.When looking at the PPVs, it can be nothed that only pTau217 yield reasonably metrics in comparison to this population's rate of tau-PET positivity (46%).Confidence intervals were derived with bootstrapping (n=100).PET = positron emission tomography; Aβ = amyloidbeta; pTau = phosphorylated tau; NfL = neurofilament light; GFAP = glial fibrillary acidic protein.

Supplementary Figure 1 .
Combining age and APOE ε4 status to individual biomarkers did not lead to increases in saved scans.These forest plots indicate the percentage point difference in the proportion of avoided scans when comparing the effect of combining age and APOE ε4 status to each biomarker versus each individual biomarker without these covariates.Biomarkers are on the y-axis, and the x-axis corresponds to the difference in saved scans in the model with covariate compared with each individual biomarker alone.Results are shown on the top row for BioFINDER-2 (n=548) and bottom row for TRIAD (n=179).Each of the panels corresponds to this difference when evaluating a certain sensitivity strategy for the screening cutoffs.The 95% confidence intervals were derived with bootstrapping (n=100).The dashed line corresponds to no difference in saved scands by adding these covariates.Source data are provided as a Source Data file.PET = positron emission tomography; Aβ = amyloid-beta; pTau = phosphorylated tau; NfL = neurofilament light; GFAP = glial fibrillary acidic protein; APOE = apolipoprotein E. results in terms of positive predictive values.This figure shows the percentage of tau-PET positive individuals within the group theoretically refered to a tau-PET scan with each biomarker, i.e. the positive predictive value (PPV).This is shown for BioFINDER-2 patients, with tau-PET positivity defined with a validated visual read method (n=539).The PPVs are shown for different screening strategies varying at sensitivity values (90%, 95%, 97.5%), and the dashed line represents the prevalence of tau-PET positivity defined with the visual read method (47%).Source data are provided as a Source Data file.PET = positron emission tomography; Aβ = amyloid-beta; pTau = phosphorylated tau; NfL = neurofilament light; GFAP = glial fibrillary acidic protein.Supplementary Figure 4. Tau-PET scans avoided and screening accuracy in SCD-MCI individuals in BioFINDER-2 and TRIAD.The top panels show the percentage of tau-PET scans saved when screening SCD-MCI individuals for tau-PET-positivity in BioFINDER-2 (n=316) and TRIAD (n=95).This metric is shown for each biomarker with screening strategies varying at sensitivity values (90%, 95%), with confidence intervals derived from 100 bootstrap trials.The bottom panel shows the positive predictive value (PPV) for each evaluated plasma biomarker at different sensitivity thresholds (90%, 95%).PPV represents the percentage of true positive tau-PET scans that can be expected among those individuals who are selected for PET scanning via plasma biomarker screening.The vertical dashed line indicates the prevalence of tau-PET positivity among the whole SCD-MCI population in BioFINDER-2 (21.2%) and TRIAD (30.5%).While PPV's for most biomarkers cross the line, plasma pTau217 was the biomarker with the best capacity to increase costeffectiveness for tau PET screening in memory clinics.Source data are provided as a Source Data file.PET Supplementary Figure 5. Tau-PET scans avoided and screening accuracy in all-cause dementia individuals in BioFINDER-2 and TRIAD.The top panels show the percentage of tau-PET scans saved when screening all-cause dementia individuals for tau-PET-positivity in BioFINDER-2 (n=232) and TRIAD (n=84).This metric is shown for each biomarker with screening strategies varying at sensitivity values (90%, 95%), with confidence intervals derived from 100 bootstrap trials.The bottom panel shows the positive predictive value (PPV) for each evaluated plasma biomarker at different sensitivity thresholds (90%, 95%).PPV represents the percentage of true positive tau-PET scans that can be expected among those individuals who are selected for PET scanning via plasma biomarker screening.The vertical dashed line indicates the prevalence of tau-PET positivity among the whole all-cause dementia population in BioFINDER-2 (57.8%) and TRIAD (59.5%).Source data are provided as a Source Data file.PET = positron emission tomography; Aβ = amyloid-beta; pTau = phosphorylated tau; NfL = neurofilament light; GFAP = glial fibrillary acidic protein.

Table 1 .
Negative and positive predictive values for each biomarker and screening strategy in BioFINDER-2.

Table 2 .
Negative and positive predictive values for each biomarker and screening strategy in TRIAD.

Table 3 .
Negative and positive predictive values for tau-PET positivity defined with visual read in BioFINDER-2.